PROJECT SUMMARY/ABSRTACT The primary goal of this research project will be the development of designed mediators for selective electrochemical oxidation of sp3 C?H bonds, through the use of descriptive statistical modeling. Remote C?H oxidation strategies are highly desirable from a synthetic standpoint and have implications for human health because of the potential for late stage derivatization of drugs. However, remote C?H functionalization methodologies have been plagued with low levels of selectivity, compared to the high levels of selectivity that have become the standard in modern organic synthesis. To address this complex problem, an intensive study into the molecular properties which bring about selectivity for C?H activation processes will be undertaken. Pyridine N-oxide and its derivatives will be evaluated as a new potential class of redox mediators (Aim 1). In order to correlate structural and electronic properties of C?H oxidation mediators with selectivity, a library of PNO derivatives will be synthesized and site-selectivity data (??G?) will be collected using model substrates that have varying complexity. Electrochemical oxidation of PNO derivatives would produce highly electrophilic radical intermediates capable of abstracting electron rich sp3 C?H bonds. In the presence of molecular oxygen, a net C?H oxidation is expected. The PNO scaffold provides the modularity required to build a large library of derivatives containing wide variation in steric/electronic properties. Steric parameters, such as Sterimol values, are predicted to produce linear free-energy relationships that correlate to selectivity differences between 2 and 3 C?H bonds, or between sterically differentiated 2 C?H bonds. Electronic parameters, such as bond stretching frequencies, could correlate to selectivity differences between electronically differentiated C?H bonds. The effects of each of these parameters on selectivity can then be combined using linear regression algorithms to produce mathematical models that will allow identification of specific mediator characteristics which control site selectivity. A key tenet of this approach is that all data points for selectivity will be included in the model, because negative results (i.e. poor selectivity or selectivity for the wrong C?H bond) also give valuable information about site-selectivity. A statistically robust model for selectivity will allow for the informed design of new mediators with improved site selectivity. Improved mediators will be evaluated for their ability to facilitate site selective C?H oxidation in a wider variety of substrates containing sterically and electronically differentiated C?H bonds. Additionally, a similar strategy will be concurrently pursued using 1,4-diazabicyclo[2.2.2]octane (DABCO) based derivatives (Aim 2). DABCO derivatives are expected to be relatively easily synthesized, providing a general structure for producing a library of steric and electronic variants. This will allow for the generation of a different set of parameters than those obtained for PNO mediators and thus more conclusions about important structural features can be made. The use of two different mediator scaffolds could lead to the development of a ?toolbox? of redox mediators that could be used to select for different types of C?H bonds.